BackgroundDuchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low‐dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate‐dose spironolactone versus eplerenone would provide similar cardioprotection in this first head‐to‐head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial.Methods and ResultsThis was a multicenter, double‐blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12–18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, −0.4 to 0.6] versus 0.2 [interquartile range, −0.2 to 0.7]; P=0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm.ConclusionsIn boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.

Background Conduction disease and arrhythmias represent a major cause of mortality in myotonic muscular dystrophy type 1 (MMD1). Permanent pacemaker (PPM) implantation is the cornerstone of therapy to reduce cardiovascular mortality in MMD1. Cardiovascular magnetic resonance (CMR) studies demonstrate a high prevalence of myocardial fibrosis in MMD1, however the association between CMR myocardial fibrosis with late gadolinium enhancement (CMR-LGE) and surface conduction abnormality is not well established in MMD1. We investigated whether myocardial fibrosis by CMR-LGE is associated with surface conduction abnormalities meeting criteria for PPM implantation according to current guidelines in a cohort of patients with genetically confirmed MMD1. Methods Patients with genetically confirmed MMD1 were retrospectively evaluated. 12-lead electrocardiography (ECG) performed within 6 months of CMR was necessary for inclusion. The severity and extent of MMD1 was quantified using a validated Muscular Impairment Rating Scale (MIRS). Based on current guidelines for device-based therapy of cardiac rhythm abnormalities, we defined surface conduction abnormality as the presence of ECG alterations meeting criteria for PPM implant (class I or II indications): PR interval > 200 ms (type I atrioventricular (AV) block) and/or mono or bifascicular block (QRS > 120 ms), or evidence of advanced AV block. Balanced steady-state free precession sequences (bSSFP) were used for assessment of left ventricular (LV) volumes and ejection fraction. MOdified Look-Locker Inversion Recovery (MOLLI) acquisition schemes were used to acquire T1 maps. Patients’ charts were reviewed up to 12 months post-CMR for occurrence of PPM implantation. Results Fifty-two patients (38% male, 41 ± 14 years) were included. Overall, 31 (60%) patients had a surface conduction abnormality and 22 (42%) demonstrated midwall myocardial fibrosis by CMR-LGE. After a median of 57 days from CMR exam, 15 patients (29%) underwent PPM implantation. Subjects with vs. without surface conduction abnormality had significantly longer disease length (15.5 vs. 7.8 years, p = 0.015) and higher disease severity on the MIRS scale ( p = 0.041). High prevalence of myocardial fibrosis by CMR-LGE was detected in subjects with and without surface conduction abnormality with no significant difference between the two cohorts (42% vs. 43%, p = 0.999). By multivariate logistic regression analysis, disease length was the only independent variable associated with surface conduction abnormality (OR 1.071, 95%CI 1.003–1.144, p = 0.040); while CMR-LGE was not associated with conduction abnormality (ρ = − 0.009, p = 0.949). Conclusions Myocardial fibrosis by CMR-LGE is highly prevalent in MMD1 but not related to surface conduction abnormality meeting current...

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Background: Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. Methods and results: Literature-based meta-analysis of prospective observational studies with ≥ 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I 2 statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person-years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15-1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. Conclusions: Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD. Review criteriaEndothelial dysfunction has been proposed as a marker of incident cardiovascular disease (CVD) outcomes, and endothelial function assessments have been considered to represent a useful tool in the evaluation of cardiovascular risk among various individuals. However, epidemiological studies evaluating this association have yielded inconsistent results to date. Message for the clinicBy combining published information on over 17,000 individuals from 35 prospective studies, we found that people within the highest category of endothelial dysfunction had just 25% excess risk of CVD outcomes, as compared with those within the lowest category. Therefore, although endothelial dysfunction may be an important determinant of vascular disease outcomes in people with pre-existing CVD, current evidence does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD.

IntroductionType 2 diabetes mellitus (T2D) confers high atherosclerotic cardiovascular disease (ASCVD) risk. The metabolite trimethylamine N-oxide (TMAO) derived via gut flora has been linked to excess ASCVD.Research design and methodsWe analyzed data, biospecimens, and major adverse cardiovascular events (MACEs) from the prospective multicenter randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess its value in 330 high-risk individuals with T2D without evident atherosclerotic disease at enrollment.ResultsIncident cardiovascular events occurred in 165 cases; 165 controls matched by age, sex, and treatment arm experienced no incident events during follow-up. Cases and controls (mean age 64.5 years) had similar mean glycated hemoglobin (HbA1c) (8.2%) and mean 10-year ASCVD risk (23.5%); groups also had similar use of statins and antihypertensive medications at baseline and follow-up. Baseline plasma TMAO levels did not differ between groups after adjusting for ASCVD risk score, HbA1c, and estimated glomerular filtration rate, nor did TMAO distinguish patients suffering incident MACE from those who remained event-free.ConclusionsTMAO’s prognostic value for incident ASCVD events may be blunted when applied to individuals with T2D with poor glycemic control and high baseline ASCVD risk. These results behoove further translational investigations of unique mechanisms of ASCVD risk in T2D.

BackgroundT‐wave abnormalities are common during the acute phase of non‐ST‐segment elevation acute coronary syndromes, but mechanisms underlying their occurrence are unclear. We hypothesized that T‐wave abnormalities in the presentation of non‐ST‐segment elevation acute coronary syndromes correspond to the presence of myocardial edema.Methods and ResultsSecondary analysis of a previously enrolled prospective cohort of patients presenting with non‐ST‐segment elevation acute coronary syndromes was conducted. Twelve‐lead electrocardiography (ECG) and cardiac magnetic resonance with T2‐weighted imaging were acquired before invasive coronary angiography. ECGs were classified dichotomously (ie, ischemic versus normal/nonischemic) and nominally according to patterns of presentation: no ST‐ or T‐wave abnormalities, isolated T‐wave abnormality, isolated ST depression, ST depression+T‐wave abnormality. Myocardial edema was determined by expert review of T2‐weighted images. Of 86 subjects (65% male, 59.4 years), 36 showed normal/nonischemic ECG, 25 isolated T‐wave abnormalities, 11 isolated ST depression, and 14 ST depression+T‐wave abnormality. Of 30 edema‐negative subjects, 24 (80%) had normal/nonischemic ECGs. Isolated T‐wave abnormality was significantly more prevalent in edema‐positive versus edema‐negative subjects (41.1% versus 6.7%, P=0.001). By multivariate analysis, an ischemic ECG showed a strong association with myocardial edema (odds ratio 12.23, 95% confidence interval 3.65‐40.94, P<0.0001). Among individual ECG profiles, isolated T‐wave abnormality was the single strongest predictor of myocardial edema (odds ratio 23.84, 95% confidence interval 4.30‐132, P<0.0001). Isolated T‐wave abnormality was highly specific (93%) but insensitive (43%) for detecting myocardial edema.ConclusionsT‐wave abnormalities in the setting of non‐ST‐segment elevation acute coronary syndromes are related to the presence of myocardial edema. High specificity of this ECG alteration identifies a change in ischemic myocardium associated with worse outcomes that is potentially reversible.

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